The major thrust of this proposal is to continue our work on various aspects of shock and hypoxia, which are of particular importance for the surfical patient. Our prevoius observations of changes in cellular and sub-cellular functions following shock and correction of some of those functions will serve as the basis on which we now plan to determine: a) the role humoral factors play in producing such changes; b) the interrelationships and perhaps interdependence of such changes, parricularly of cellular energetics and membrane function; c) the reason for organ failure, partucularly muscle and liver cellular metabolic and mitochondrial failure in late sepsis and with multiple systems failure; d) the sequences of and reasons for remote organ failure with sepsis; e) the reason for depressed immunocompetence following burn trauma; and f) further therapeutic considerations aimed at improving cell function and the mechanisms for this. Specific areas of activity include: 1) the role epinephrine plays in producing hepatic depolarization, metabolic depression, insluin resistance and alterations in membrane permeabilityu with shock; 2) evaluation of the role of the thyroid in late sepsis and organ failure and the possibility of "myxedematous mitochondria" causing the terminal metabolic failure of muscle and liver; 3) further study of the precise mechanism by which high energy phosphate compounds produce salutary effects; 4) characterization, kinetics and localization of adenine nucleotide uptake in the cell and determination of a potential transport carrier system; 5) further studies to determine critical energy levels for various aspects of cell function; 6) necessary background information for clinical trials of ATP-MgC12; 7) the status of calcium regulation in low flow conditions; 8) the nature of alterations in hepatic metabolic capabilities in sepsis; 9) study of kidney preservation following normothermic ischemia; 10) whether creatine phosphate or other substrates will help prevent ischemic damage to the heart during coronary insufficiency and to the central nervous system during and after an acute ischemic insult; 11) study of tuftsin on increased pulmonary retention of particulate matter following splenectomy and sepsis; and 12) whether therapy involving ablations of precursors of suppressor-T cells would improve the resistance to infection following burn injury.